Text-Atlas of Skeletal Age Determination: MRI of the Hand and Wrist in Children

By Ernesto Tomei, Richard C. Semelka and Daniel Nissman

The first complete textbook and atlas of the vitally important technique of bone age assessment utilizing MRI for children's hand and wrist

This latest volume in the growing Wiley Current Clinical Imaging series is a must-have resource that collects, in a single volume, all that is currently known and applicable about the use of magnetic resonance imaging (MRI) for the assessment of bone age.

Presented in two parts, Text-Atlas of Skeletal Age Determination: MRI of the Hand and Wrist in Children first focuses on the anatomic, social, and legal aspects of bone age, providing a concise overview of the use of bone age determination in medical, legal, and social systems.??It then covers the clinical use and application of MRI in assessing bone age. The book offers complete chapter coverage on endocrinology, puberty, and disorders of pubertal development; bone marrow maturation in healthy and diseased states; growth failure and pediatric inflammatory bowel disease; skeletal findings in neurometabolic disease, genetic disease, and pediatric oncology patients; and much more.

Text-Atlas of Skeletal Age Determination provides:

• A comprehensive review of the medical, legal, and social aspects of bone age assessment
• An in-depth discussion of MRI as an alternative to the traditional ionizing radiation-based radiographic techniques for the assessment of bone age
• Complete guidelines for clinical application of these MRI-based techniques
• "Recipes" for replicating these techniques and applications for diverse patient populations
• Cutting-edge information prepared and presented by an international team of experts
• A superb collection of beautifully reproduced, high-quality images

This is an ideal book for radiologists, pediatricians, family physicians, endocrinologists, and sports medicine physicians interested in skeletal development and bone age assessment.

• Language: English
• Publisher: Wiley
• Release date: Nov 19, 2013
• ISBN: 9781118692141

Book preview

Contributors

Najwa Al Ansari, MD

Resident at Department of Radiology, Oncology and Anatomy Pathology

Sapienza University of Rome

Rome, Italy

Carlina V. Albanese, MD

Associate Professor of Radiology

Head of Osteoporosis Unit

Department of Radiological Sciences, Oncology and Pathology

Sapienza University of Rome

Rome, Italy

Marina Aloi, MD

Pediatric Gastroenterology and Liver Unit

Department of Pediatrics

Sapienza University of Rome

Rome, Italy

Paolo Arbarello, MD

Full Professor of Forensic Medicine;

Director of the Forensic Medicine Section in the Department of Anatomical, Histological, Forensic and Orthopaedic Sciences

Sapienza University of Rome;

Director of Postgraduate course in Forensic Medicine

Sapienza University of Rome;

President of SIMLA (Italian Society of Forensic Medicine)

Rome, Italy

Sofia Battisti, MD

Clinical Research Scholar

MR Section, Department of Radiology

University of North Carolina

Chapel Hill, North Carolina, USA;

Resident Radiology

Department of Radiology Campus Bio-medico of Rome

Rome, Italy

Maria Bavestrelli, MD

Department of Pediatrics and Infantile Neuropsychiatry

Sapienza University of Rome

Rome, Italy

Sara Bertino, MD

Child Neurology Division

Department of Pediatrics and Child Neurology and Psychiatry

Sapienza University of Rome

Rome, Italy

Margherita Bonamico, MD

Associate Professor

Department of Pediatrics and Infantile Neuropsychiatry

Sapienza University of Rome

Rome, Italy

Carlo Alberto Cappelli, MD

Oncology Unit

Department of Pediatrics

Sapienza University of Rome

Rome, Italy

Vincenzo Carnevale, MD

Internal Medicine Unit,

Casa Sollievo della Sofferenza Hospital

IRCCS, San Giovanni Rotondo (FG)

Italy

Guido Carpino, MD

Department of Motor, Human and Health Sciences

University of Rome Foro Italico

Rome, Italy

Anna Clerico, MD PhD

Associate Professor

Oncology Unit

Department of Pediatrics

Sapienza University of Rome

Rome, Italy

Fiorenza Colloridi

Assistant Professor

Department of Pediatrics

Clinical Genetics Unit

Sapienza University of Rome

Rome, Italy

Salvatore Cucchiara, MD

Full Professor

Pediatric Gastroenterology and Liver Unit

Department of Pediatrics

Sapienza University of Rome

Rome, Italy

Brian M. Dale, PhD

Zone Research Manager

MR R&D Collaborations

Siemens Medical Solutions, Inc.

Morrisville, North Carolina, USA

Lorenzo Maria Donini, MD

Associate Professor

Section of Medical Pathophysiology, Endocrinology and Nutrition

Department of Experimental Medicine

Sapienza University of Rome;

Unit of Endocrinology Section of Health Sciences

University of Rome Foro Italico

Rome, Italy

Eugenio Gaudio, MD

Full Professor

Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences

Sapienza University of Rome

Rome, Italy

Andrea Laghi, MD

Associate Professor of Radiology

Department of Radiology, Oncology and Anatomy Pathology

Sapienza University of Rome

Rome, Italy;

Director, Tecniche Diagnostiche Avanzate

Instituto Chirurgico Ortopedico Traumatologico

Latina, Italy

Andrea Lenzi, MD

Full Professor

Department of Experimental Medicine

Section of Medical Pathophysiology, Food Science and Endocrinology

Sapienza University of Rome

Rome, Italy

Vincenzo Leuzzi, MD

Child Neurology Division

Department of Pediatrics and Child Neurology and Psychiatry

Sapienza University of Rome

Rome, Italy

Natascia Liberati, student

Department of Pediatrics

Clinical Genetics Unit

Sapienza University of Rome

Rome, Italy

Chiara Mancini, MD

Department of Pediatrics

Clinical Genetics Unit

Sapienza University of Rome

Rome, Italy

Francesca Mancini, MD

Department of Pediatrics

Clinical Genetics Unit

Sapienza University of Rome

Rome, Italy

Michela Martini, MD

Department of Pediatrics

Clinical Genetics Unit

Sapienza University of Rome

Rome, Italy

Milvia Martino

Department of Radiology, Oncology and Anatomy Pathology

Sapienza University of Rome

Rome, Italy

Mario Mastrangelo, MD PhD

Child Neurology Division

Department of Pediatrics and Child Neurology and Psychiatry

Sapienza University of Rome

Rome, Italy

Chiara Mattiucci, MD

Department of Pediatrics

Clinical Genetics Unit

Sapienza University of Rome

Rome, Italy

Silvia Migliaccio, MD

Section of Medical Pathophysiology, Endocrinology and Nutrition

Department of Experimental Medicine

Sapienza University of Rome;

Unit of Endocrinology Section of Health Sciences

University of Rome Foro Italico

Rome, Italy

Salvatore Minisola, MD

Full Professor

Department of Internal Medicine

Policlinico Umberto I Hospital

Sapienza University of Rome

Rome, Italy

Monica Montuori, MD PhD

Department of Pediatrics and Infantile Neuropsychiatry

Sapienza University of Rome

Rome, Italy

Daniel B. Nissman, MD MPH MSEE

Clinical Assistant Professor of Radiology

Department of Radiology, Musculoskeletal Section

UNC School of Medicine

Chapel Hill, North Carolina, USA

Giovanni Parlapiano, student

Department of Pediatrics

Clinical Genetics Unit

Sapienza University of Rome

Rome, Italy

Leonardo Pimpolari, MD

Department of Pediatrics

Clinical Genetics Unit

Sapienza University of Rome

Rome, Italy

Alessandro Pinto, MD

Section of Medical Pathophysiology, Endocrinology and Nutrition

Department of Experimental Medicine

Sapienza University of Rome;

Unit of Endocrinology Section of Health Sciences

University of Rome Foro Italico

Rome, Italy

Antonio Radicioni, MD

Professor, Department of Experimental Medicine

Section of Medical Pathophysiology, Food Science and Endocrinology

Sapienza University of Rome

Rome, Italy

Antonello Rubini, MD

Department of Radiology, Oncology and Anatomy Pathology

Sapienza University of Rome

Rome, Italy

Gilda Ruga, MD

Department of Experimental Medicine

Section of Medical Pathophysiology, Food Science and Endocrinology

Sapienza University of Rome

Rome, Italy

Alessandro Sartori, MD

Resident at Department of Radiology, Oncology and Anatomy Pathology

Sapienza University of Rome,

Rome, Italy

Richard C. Semelka, MD

Professor of Radiology;

Director of Magnetic Resonance Services;

Vice Chair of Quality and Safety

Department of Radiology

UNC School of Medicine

Chapel Hill, North Carolina, USA

Serenella Serinelli, MD

Resident in Forensic Medicine

Sapienza University of Rome

Rome, Italy

Luigi Tarani, MD

Professor, Department of Pediatrics

Clinical Genetics Unit

Sapienza University of Rome

Rome, Italy

Ernesto Tomei, MD

Associate Professor of Radiology

Department of Radiology, Oncology and Anatomy Pathology

Sapienza University of Rome,

Rome, Italy

Giulia Varrasso, MD

Oncology Unit

Department of Pediatrics

Sapienza University of Rome

Rome, Italy

Introduction

The radiographic examination of the hand and wrist was initially used to study skeletal development, correlating skeletal and chronologic age in order to verify potential growth and whether a need for intervention was necessary. In recent years, the reasons for this examination has expanded beyond assessment of development, into such areas as the law, sports, and delving more deeply into nonimaging specialties, including pediatric endocrinology, gastroenterology, hematology, oncology, genetics, and metabolics.

The increase in the interest and importance of imaging in these evaluations, combined with the awareness of the potential harm from X-rays, especially in young individuals, has prompted the scientific community to consider diagnostic modalities that do not involve ionizing radiation. In addition to avoiding the use of radiation, MRI has the additional potentially tremendous value, because its intrinsic high soft tissue contrast resolution, of providing unique information on the bone marrow, cartilage, and muscles and soft tissues.

In this text-atlas, the editors and collaborators describe their early and ground-breaking work into the use of MRI to evaluate bone, bone marrow, and cartilage, to assess MR skeletal age both in normal subjects and in individuals with disease. The chapters that illustrate normal bone age present strategies comparable to both traditional Greulich and Pyle and Tanner and Whitehouse approaches, but with far greater information, due to the capacity of MRI to reveal the appearance of all the developing musculoskeletal tissues. Chapters written by a variety of clinical specialist experts also point the direction towards greater integration of MRI findings into management of patients with a full range of disease processes. The potential applications in safe use of detailed imaging in children seems endless, and for this reason it is a great pleasure for me to present this work as a longtime colleague and friend of Professor Tomei.

Professor Roberto Passariello

Preface

The unmatched soft tissue contrast resolution of MRI has been recognized since the inception of clinical MRI in the mid 1980s. Also recognized since the early days is the tremendous ability of MRI to reveal the various components of the musculoskeletal system, including bone marrow, ligaments, tendons, and cartilage. Although MRI has been widely used for evaluating the changes in bone in the growing skeleton of children, there is relatively little work attempting to provide a comprehensive vision on assessing skeletal age throughout childhood. In this book we formalize our 3-year experience with using MRI to evaluate skeletal age in healthy subjects and in children with a variety of underlying diseases, including genetic disease, cancer, celiac disease, and Crohn disease. A low field open magnet (0.2 Tesla) was used for this study; coronal 3D spin echo T1-weighted images with a slice thickness of 1.3 mm were acquired.

We have used the left wrist and hand of children to assess skeletal age, basing this upon the convention used originally by Greulich and Pyle and subsequently by Tanner and Whitehouse. Building upon their work, we have not only studied the development of ossified bone, but now, thanks to the soft tissue resolving capacity of MRI, we have expanded our assessment to include cartilage and bone marrow, and their changes with maturation. By this means we believe that this approach will be the most accurate means by which to determine skeletal age, based on the variety of information assessed and the detail that can be visualized. Determination of skeletal age is not only important for children who may experience what appears to be either delayed or premature growth, but also to verify the age of individuals, which also has medicolegal implications. We include in this book a new field of research, the effects of physical activity and excess physical activity as a potential area of considerable importance for athletic pursuits.

The key aspect of this work is our efforts to categorize and systematize the observations of normal development of bones, describing in detail the various stages of maturation of cartilage, ossification centers, and bone marrow. These evaluations were not previously accessible in vivo until detailed evaluation by MRI. This forms the framework for our early development of the Tomei skeletal aging system.

We have addressed a variety of different disease processes that can result in delayed growth and also premature growth. In this edition we introduce evaluating delay or prematurity from the concept of growth abnormality with usual pattern of development, growth abnormality with abnormal pattern of development, and growth abnormality with development of abnormal bones.

Sir Isaac Newton is credited with remarking: If I have seen further it is by standing on the shoulders of giants, by this same fashion we credit our predecessors who determined skeletal age by using imaging studies.

In working with young children, safety is of paramount importance. We believe this is one of the compelling strengths of MRI, because no ionizing radiation is used. At the same time, because children make up the source material of the book, we were very careful to obtain approval from the institutional ethics committee, but most importantly from the parents and other care-givers. Additionally, some of the studies in patients with various clinical diseases were for clinical reasons and not research.

Lastly, we wish to acknowledge the work of our MR technologists in performing these studies, with special thanks to Antonio Moscato and Roberto Fringuelli, and to Serena Sposato, who is in charge of medical records for the Department of Radiology at La Sapienza.

Ernesto Tomei, Sofia Battisti, Milvia Martino, Daniel B. Nissman, and Richard C. Semelka

CHAPTER 1

Anatomic Aspects of Bone Ossification and their Magnetic Resonance Counterparts

Guido Carpino¹, Ernesto Tomei², Richard C. Semelka³, and Eugenio Gaudio⁴

¹Department of Motor, Human and Health Sciences, University of Rome Foro Italico, Rome, Italy

²Department of Radiology, Oncology and Anatomy Pathology, Sapienza University of Rome, Rome, Italy

³Department of Radiology, UNC School of Medicine, Chapel Hill, North Carolina, USA

⁴Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, Rome, Italy

1.1 Endochondral ossification

Endochondral ossification is the process by which a bone develops from a pre-existing model composed of hyaline cartilage. It begins around the sixth week of fetal development and continues into the individual's twenties. Most bones of the body, including the vertebrae, ribs, sternum, scapula, pelvis, and bones of the limbs, develop in this way [1,2].

Ossification proceeds in the following fashion: the center of the cartilage model is invaded by mesenchymal stem cells which form the primary center of ossification. Later, at each end of the cartilage model, secondary centers of ossification appear (Figure 1.1). These centers of ossification gradually encroach on the remaining cartilage, ultimately replacing it completely (except at the articular surfaces) by the time skeletal maturity is reached [1,3,4]. The cartilage model is important as the source of longitudinal bone growth. The ossification of the cartilage model is a well-organized process which could be subdivided into several phases [1,3,4].

Figure 1.1 Endochondral ossification is the process. To see a color version of this figure, please see Plate 1.1.

c1-fig-0001

1.1.1 Primary center of ossification (fetal life)

Chondrocytes at the center of the cartilaginous model (the diaphysis) begin to increase in number and size. The chondrocytes' hypertrophy is followed by their apoptosis, matrix calcification, and vascular invasion. The blood vessels bring with them mesenchymal stem cells that will give rise both to osteoblasts and osteoclasts. The invading cells stimulate the removal of the calcified cartilage and its replacement by trabecular bone and bone marrow.

1.1.2 Growth plate

As the bone marrow cavity expands toward the epiphyses, the chondrocytes at the epiphyseal margin proliferate rapidly, forming longitudinal columns of flattened cells. Thus, the primary growth plate is interposed between the cartilaginous epiphysis and the newly generated bone (bone marrow cavity). The growth plate is composed of zones of resting, proliferative, maturing, and hypertrophic chondrocytes, and of calcification.

Zone of resting cartilage. This region, farthest from the marrow cavity, consists of typical hyaline cartilage that as yet shows no sign of transforming into bone.

Zone of cell proliferation. A little closer to the marrow cavity, chondrocytes multiply and arrange themselves into longitudinal columns of flattened lacunae.

Zone of cell hypertrophy. Next, the chondrocytes cease to divide and begin to hypertrophy.

Zone of calcification and bone deposition. Minerals are deposited in the matrix between the columns of lacunae and calcify the cartilage. Apoptosis of hypertrophic chondrocytes occurs. Each column is converted into a longitudinal channel, which is immediately invaded by blood vessels and marrow from the marrow cavity. Osteoblasts line up along the walls of these channels and begin depositing concentric lamellae of matrix, while osteoclasts dissolve the temporarily calcified cartilage.

Within the growth plate, chondrocyte proliferation (zone of cell proliferation) is balanced by chondrocyte apoptosis and the replacement of the calcified cartilage with bone (zone of bone deposition). In this way, the width of the growth plate during development is maintained while the bone increases in length [1,3,4].

1.1.3 Secondary centers of ossification (later in development)

Roughly spherical secondary centers of ossification form within the cartilaginous epiphyses. The secondary ossification center becomes hollowed out by the same process as occurs in the diaphysis, generating a secondary marrow cavity in the epiphysis. This cavity expands outward from the center, in all directions. In bones with two secondary ossification centers, one center lags behind the other in development, so at birth there is a secondary marrow cavity at one end while chondrocyte growth has just begun at the other [1].

The appearance and development of secondary centers of ossification is a well-organized process. It has been shown that this process is driven by vascular endothelial growth factors (VEGFs). Immediately prior to the vascular invasion of the epiphysis, a positive reaction to VEGF is localized in chondrocytes of the epiphyseal cartilage close to the capsule insertion. During the development and expansion of the secondary ossification center, VEGF expression is higher in chondrocytes but decreases when the epiphysis is diffusely ossified. VEGF is also expressed by mesenchymal cells present in and around the fibrous tissue where the secondary ossification center will develop [2,5].

Vascular corrosion casts confirm that vessels that penetrate into the epiphysis arise primarily from the periosteal and capsular networks, and vascular connections with the diaphyseal circulation are not evident. Hence the epiphyseal microcirculation is distinct from that of the diaphysis, and arises from the vessels present in the capsule and the periosteal networks. In young animals the only capillaries are bone marrow sinusoids and a few subchondral capillaries. In adult animals small vessels run between the clusters of sinusoids forming the trabecular circulation. Capillary sprouts from sinusoids are observed both in young and adult animals. Thus, in adults, different proper microcirculatory districts can be distinguished in the epiphysis: (i) the sinusoidal network, which supplies the hematopoiesis of the bone marrow and the adjacent osteogenic tissue, and (ii) the bone tissue microcirculation, limited to small vessels that supply the metabolism and the remodeling of bone tissue [2,5,6].

These observations demonstrate that VEGF production by chondrocytes begins a few days after birth, supports the rapid vascular growth from the surrounding soft tissues, and is chronologically related to the development of the secondary ossification centers [2,5,6].

The microvascular organization and its adaptation to epiphyseal growth represents the morphologic basis for understanding the interaction between the different tissues in developing and adult epiphyses, with most of the basic research performed on the rat model [2,5,6].

1.2 Longitudinal bone growth

Longitudinal bone growth continues until puberty when chondrocyte proliferation ceases and the primary and secondary centers of ossification fuse. A thin layer of cartilage covering the joint surface remains throughout adulthood, protecting the underlying bone and providing a smooth surface for articulation [1,3,4].

The region of transition from cartilage to bone at each end of the primary marrow cavity is called the metaphysis. By the late teens to early twenties, all remaining cartilage in the epiphyseal plate is generally consumed and the gap between the epiphysis and diaphysis closes. The primary and secondary marrow cavities then unite into a single cavity, and the bone can no longer grow in length [1,3,4].

The junctional region where they meet is filled with spongy bone, and the site of the original epiphyseal plate is marked with a line of slightly denser spongy bone called the epiphyseal line.

When the epiphyseal plate is depleted, the epiphysis has closed because no gap between the epiphysis and diaphysis is visible on X-ray. The epiphyseal plates close at different ages in different bones and in different regions of the same bone. The state of closure in various bones is often used in forensic science to estimate the age at death of a subadult skeleton [1,3,4].

1.3 Magnetic resonance aspects of endochondral ossification

Magnetic resonance (MR) imaging can study in detail the dynamic process of skeletal growth and maturation [7]. The bone cortex is of very low signal intensity (SI) on images obtained with all sequences (Figures 1.2 and 1.3). The periosteum can be observed as a thin, low-SI, linear structure that parallels the bone cortex; this appearance is due to its composition of collagen fibers, fibroblasts, and osteoprogenitor cells. The articular cartilage is a highly organized form of hyaline cartilage and can be observed on water-sensitive images as a thin hyperintense rim surrounding the less well-organized hyaline cartilage of the developing epiphysis (Figures 1.2 and 1.3). Moreover, it can show details on: (i) bone marrow conversion, (ii) epiphyseal cartilage, and (iii) growth plate [7].

Figure 1.2 Anatomy of the wrist and its magnetic resonance (MR) counterpart: (a) anatomic drawing of wrist and hand bones; (b) magnetic resonance image (MRI of the wrist in a 17-year-old male. The MR aspect of bone cortex, ossification center, articular cartilage, and growth plate are visible. Bone cortex is characterized by a low signal intensity (SI); the ossification center has a high SI due to its content in adipose (yellow) bone marrow and possesses an outer bony shell (low intensity). The articular cartilage is characterized by a homogeneous intermediate SI. The growth plate of the distal radius is well shown. The zone of calcification is recognizable by its low SI. This zone contains matrix that is highly mineralized. In the growing healthy child, the zone of calcification should be continuous and uniform. In infants and young children, the growth plate is a flat disk. Normal growth proceeds unevenly; thus, the growth plate becomes undulating as evident in this image. The triangular ligament is indicated.

c1-fig-0002

Figure 1.3 Carpal bones develop in a pattern similar to that of the epiphyses of long bones. For this reason, these epiphyseal equivalents show early marrow conversion, develop from spherical or hemispheric physes, and can show irregular ossification. The ossification of carpal bones occurs in a predictable pattern and has been used to estimate the age and potential to grow. (a) In a 4-year-old male, the ossification centers of hamate, capitate, and pyramidal bone are present (arrows). The cartilaginous shaft of lunate, trapezoid, and scaphoid bone are recognizable (arrowheads). The epiphyseal cartilage of metacarpal bones (arrowhead) demonstrates homogeneous intermediate signal intensity (SI). The secondary center of ossification is present in the distal epiphysis of the radius (arrow) and it is characterized by an outer bony rim. (b) In an 8-year-old male, the ossification centers of lunar, trapezoid, and scaphoid bone are present (arrows). Notably, the SI of scaphoid bone is low (arrow) if compared with other bones; the lower SI could be due to early and only partial conversion of hematopoietic bone marrow to adipose bone marrow because the ossification center of the scaphoid bone appears later (approximately at age 6) in comparison with the other carpal bones. (c, d) The appearance of the vacuolization and ossification center of the pisiform bone is the last to occur and appears around the age of 10–11 years in males (arrowhead, cartilaginous shaft; arrow, ossification center). To see a color version of this figure, please see Plate 1.2.

c1-fig-0003

1.3.1 Bone marrow

Conversion from hematopoietic to fatty marrow is a well-recognized process that occurs throughout childhood in a predictable and reproducible pattern. In later pregnancy and during the first weeks of life, a larger marrow space becomes evident and the SI of the shafts of the bone reflects the marrow composition [7,8]. In the neonate, the marrow is entirely hematopoietic. Hematopoietic (red) bone marrow is mostly composed of red blood cells; however, it contains a substantial amount of fat (almost 40%) [9]. In contrast, fatty (yellow) marrow is composed of 80% fat. Owing to the exquisite sensitivity to fat of MR imaging, marrow SI reflects the fat content both in the yellow marrow and in the red marrow [7,9]. Accordingly, on T1-weighted images, the SI of normal hematopoietic marrow is low (similar to or higher than that of muscle) while high SI is present when it is converted to fatty marrow. The higher water content of hematopoietic marrow results in a higher SI on images obtained with a water-sensitive MR sequence. The conversion from red to yellow bone marrow (Figure 1.2) begins during the first year of life and is almost complete by the time of skeletal maturity in the appendicular skeleton; in contrast, this process proceeds in the axial skeleton throughout life. Marrow conversion occurs in a predictable pattern [7,9]. Within the body, the transformation occurs from the periphery (phalanges of the fingers and toes) to the center (humeri and femora). In each bone, epiphyseal conversion to fatty marrow occurs first [10] and the transformation continues in the diaphysis and proceeds as a front toward the metaphyses [9]. More detailed description of changes